In vivo differentiation of relative oxygen levels and tumor necrosis using divalent europium

1. A method of magnetic resonance imaging a target tissue in a subject, the method comprising:

a) administering a first Eu 2+ -containing complex to the subject, the first Eu 2+ -containing complex having a reduction potential that is more negative than a reduction potential for a selected compound present in the target tissue;

b) taking a first set of images of the target tissue in the subject by T 1 -weighted magnetic resonance imaging;

c) administering a second Eu 2+ -containing complex to the subject, the second Eu 2+ -containing complex having a reduction potential that is more positive than a reduction potential for the selected compound present; and

d) taking a second set of images of the target tissue in the subject by T 1 -weighted magnetic resonance imaging.

2. The method of claim 1 wherein the first Eu 2+ -containing complex includes a europium metal ion (Eu 2+ ) and a multi-dentate ligand selected from the group consisting of cryptands and thiacryptands and counter-ions to maintain charge neutrality.

3. The method of claim 2 wherein the multi-dentate ligand is described by formula I:

wherein:

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently O or S;

R 1 , R 2 , R 3 are each independently H, C 1-12 alkyl, C 1-12 alkynyl, C 1-12 alkenyl, C 1-12 fluoroalkyl, Cl, F, Br, nitro, cyano, or C 6-14 aryl, C 5-14 hetereoaryl, or 5 and 6 membered rings formed by combining R 1 on adjacent carbon atoms or R 2 and R 3 on adjacent carbon atoms, ═O by combining R 1 , R 2 , or R 3 on the same carbon atom, ═S by combining R 1 , R 2 , or R 3 on the same carbon atom, or ═NR by combining R 1 , R 2 , or R 3 on the same carbon atom; and

R is H or C 1-12 alkyl.

4. The method of claim 2 wherein R 1 , R 2 , or R 3 are each independently H, phenyl, or biphenyl.

5. The method of claim 1 wherein the first Eu 2+ -containing complex and the second Eu 2+ -containing complex to the subject are administered by intravenous, intraperitoneal, or subcutaneous injection.

6. The method of claim 1 wherein the second Eu 2+ -containing complex includes a europium metal ion (Eu 2+ ) and a multi-dentate ligand selected from the group consisting of cryptands and thiacryptands and counter-ions to maintain charge neutrality.

7. The method of claim 6 wherein the multi-dentate ligand is described by formula I:

wherein:

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently O or S;

R 1 , R 2 , R 3 are each independently H, C 1-12 alkyl, C 1-12 alkynyl, C 1-12 alkenyl, C 1-12 fluoroalkyl, Cl, F, Br, nitro, cyano, or C 6-14 aryl, C 5-14 hetereoaryl, or 5 and 6 membered rings formed by combining R 1 on adjacent carbon atoms or R 2 and R 3 on adjacent carbon atoms, ═O by combining R 1 , R 2 , or R 3 on the same carbon atom, ═S by combining R 1 , R 2 , or R 3 on the same carbon atom, or ═NR by combining R 1 , R 2 , or R 3 on the same carbon atom; and

R is H or C 1-12 alkyl.

8. The method of claim 1 wherein the target tissue is necrotic tissue.

9. A method of magnetic resonance imaging a target tissue in a subject, the method comprising:

a) administering a first Eu 2+ -containing complex to the subject, the first Eu 2+ -containing complex having a reduction potential that is more negative than a reduction potential for a selected compound present in the target tissue;

b) taking a first set of images of the target tissue in the subject by T 1 -weighted magnetic resonance imaging;

c) administering a second Eu 2+ -containing complex to the subject, the second Eu 2+ -containing complex having a reduction potential that is more positive than a reduction potential for the selected compound present;

d) taking a second set of images of the target tissue in the subject by T 1 -weighted magnetic resonance imaging; and

e) comparing the first set of images and the second set of images to identify regions that possess different concentrations of the selected compound.

10. The method of claim 9 wherein the first Eu 2+ -containing complex and the second Eu 2+ -containing complex each independently include a europium metal ion (Eu 2+ ) and a multi-dentate ligand selected from the group consisting of cryptands and thiacryptands and counter-ions to maintain charge neutrality.

11. The method of claim 10 wherein the multi-dentate ligand is described by formula I:

wherein:

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 and Y 6 are each independently O or S;

R 1 , R 2 , R 3 are each independently H, C 1-12 alkyl, C 1-12 alkynyl, C 1-12 alkenyl, C 1-12 fluoroalkyl, Cl, F, Br, nitro, cyano, or C 6-14 aryl, C 5-14 hetereoaryl, or 5 and 6 membered rings formed by combining R 1 on adjacent carbon atoms or R 2 and R 3 on adjacent carbon atoms, ═O by combining R 1 , R 2 , or R 3 on the same carbon atom, ═S by combining R 1 , R 2 , or R 3 on the same carbon atom, or ═NR by combining R 1 , R 2 , or R 3 on the same carbon atom; and

R is H or C 1-12 alkyl.

12. The method of claim 11 wherein R 1 , R 2 , or R 3 are each independently H, phenyl, or biphenyl.

13. The method of claim 9 wherein the a first Eu 2+ -containing complex and the second Eu 2+ -containing complex to the subject are administered by intravenous, intraperitoneal, or subcutaneous injection.

14. The method of claim 9 wherein the target tissue is necrotic tissue.

15. The method of claim 2 wherein R 2 and R 3 are hydrogen and one of the R 1 is not hydrogen. In other refinements, R 2 and R 3 are hydrogen and two of the R 1 are not hydrogen.

16. The method of claim 2 wherein R 2 and R 3 are hydrogen and two of the R 1 are not hydrogen.

17. The method of claim 11 wherein R 2 and R 3 are hydrogen and one of the R 1 is not hydrogen. In other refinements, R 2 and R 3 are hydrogen and two of the R 1 are not hydrogen.

18. The method of claim 11 wherein R 2 and R 3 are hydrogen and two of the R 1 are not hydrogen.